Throughout this application, various publications are referenced by author and date. Full citations for these publications may be found listed alphabetically at the end of the specification immediately following the Experimental Procedures section and preceding the claims sections. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
Ischemic heart disease is a leading cause of morbidity and mortality in the general population, but especially in patients with diabetes. The prevalence of coronary artery disease is as high as 55% in adult patients with diabetes (Robertson and Strong, 1968). Indeed, data from the Framingham Heart Study demonstrate that mortality from cardiovascular disease in non-insulin dependent diabetes (NIDDM) is more than doubled in diabetic men and more than quadrupled in diabetic women when compared with nondiabetic control subjects (Kannel and McGee, 1979). In addition to increased prevalence, studies have shown that atherosclerosis in diabetic patients is clearly more accelerated and extensive. In one autopsy series, for example, patients with diabetes were found to have more severe disease of the left anterior descending coronary artery (Waller et al., 1980), a higher incidence of two and three-vessel disease (Crall and Roberts, 1978), and a greater diffuseness of distribution of atherosclerotic lesions (Hamby et al., 1976). These findings were confirmed by coronary angiography in symptomatic patients (Pyorala et al., 1978).
The reasons for accelerated atherosclerosis in the setting of diabetes are numerous. However, even after correction for dyslipidemia, hypertension and obesity, multivariate analysis studies have indicated that diabetic patients have an excess risk of cardiovascular disease relative to nondiabetic subjects (Kannel and McGee, 1979). For example, in the Nurses"" Health Study of 1,500 diabetic subjects among a total of 115,000 women, the incidence of cardiovascular disease was 5-fold higher in the diabetic subjects regardless of their levels of cholesterol (Manson et al., 1991). These data suggest that factors unique to the diabetic population play an important role.
The pathologic hallmarks of Alzheimer""s disease (AD) are intracellular and extracellular accumulations of proteins, progression of which is closely correlated with eventual neuronal dysfunction and clinical dementia (for reviews see Goedert, 1993; Haass et al., 1994; Kosik, 1994; Trojanowski et al., 1994; Wischik, 1989). Amyloid-xcex2 peptide (Axcex2), which is the principal component of extracellular deposits in AD, both in senile/diffuse plaques and in cerebral vasculature, actively influences cellular functions as indicated by several lines of evidence: Axcex2 has been shown to promote neurite outgrowth, generate reactive oxygen intermediates (ROIs), induce cellular oxidant stress, lead to neuronal cytotoxicity, and promote microglial activation (Behl et al., 1994; Davis et al., 1992; Hensley, et al., 1994; Koh, et al., 1990; Koo et al., 1993; Loo et al., 1993; Meda et al., 1995; Pike et al., 1993; Yankner et al., 1990). For Axcex2 to induce these multiple cellular effects, cell surfaces may contain a binding protein(s) which engages Axcex2. In this context, several cell-associated proteins, as well as sulfated proteoglycans, can interact with Axcex2. These include: substance P receptor, the serpin-enzyme complex (SEC) receptor, apolipoprotein E, apolipoprotein J (clusterin), transthyretin, alpha-1 anti-chymotrypsin, xcex2-amyloid precursor protein, and sulphonates/heparin sulfates (Abraham et al., 1988; Fraser et al., 1992; Fraser et al., 1993; Ghiso et al., 1993; Joslin et al., 1991; Kimura et al., 1993; Kisilevsky et al., 1995; Strittmatter et al., 1993a; Strittmatter et al., 1993b; Schwarzman et al., 1994; Snow et al., 1994; Yankner et al., 1990). Of these, the substance P receptor and SEC receptor might function as neuronal cell surface receptors for Axcex2, though direct evidence for this is lacking (Fraser et al., 1993; Joslin et al., 1991; Kimura et al., 1993; Yankner et al., 1990). In fact, the role of substance P receptors is controversial, and it is not known whether Axcex2 alone interacts with the receptor, or if costimulators are also required (Calligaro et al., 1993; Kimura et al., 1993; Mitsuhashi et al., 1991) and the SEC receptor has yet to be fully characterized. Amyloid-xcex2 peptide (Axcex2) is central to the pathology of Alzheimer""s disease (AD), primarily because of its neurotoxic effects which involve induction of cellular oxidant stress.
The present method provides for an isolated peptide having an amino acid sequence corresponding to the amino acid sequence of a V-domain of a receptor for advanced glycation endproduct (RAGE). The present invention also provides for an isolated peptide having an amino acid sequence A-Q-N-I-T-A-R-I-G-E-P-L-V-L-K-C-K-G-A-P-K-K-P-P-Q-R-L-E-W-K (SEQ ID No: 1). The present invention provides for a pharmaceutical composition comprising a therapeutically effect amount of an isolated peptide having an amino acid sequence corresponding to the amino acid sequence of a V-domain of RAGE and a pharmaceutically acceptable carrier. The present invention also provides for a method for inhibiting interaction of an amyloid-xcex2 peptide with a receptor for advanced glycation end product which is on the surface of a cell, which comprises contacting the cell with the peptide or a functionally equivalent agent, wherein the peptide or agent is capable of inhibiting interaction of the amyloid-xcex2 peptide with the receptor for advanced glycation end product, and the peptide or agent is present in an amount effective to inhibit interaction of the amyloid-xcex2 peptide with the receptor for advanced glycation endproduct.
The present invention also provides for a method for treating a subject with a condition associated with interaction of an amyloid-xcex2 peptide with a receptor for advanced glycation end product on a cell, which comprises administering to the subject the peptide or a functionally equivalent agent capable of inhibiting the interaction of the amyloid-xcex2 peptide with the receptor for advanced glycation end product, the peptide or the agent being present in an amount effective to inhibit the amyloid-xcex2 peptide interaction with the receptor, thereby treating the subject.